Imaging in Alzheimer's Disease: The Current State of Affairs

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Introduction

Are you confused about the various forms of PET and MRI that are used to image the brain? Do you know which protocol is more suited to detecting plaques and which can measure brain activity? Are you concerned when you see images of shrinking brains? Do you know what needs to be done to improve brain imaging?

Whether you are a clinician, a molecular biologist, a caregiver or a master of magnetic resonance, join Alzforum and five imaging experts to discuss what we know, what we don't know and what we need to know in order to make imaging technology easier, more informative and routinely available.

Chet Mathis and Bill Klunk, with Julie Price, Cliff Jack, and Eric Reiman, led this live discussion on 27 April 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Live Discussion led by Bill Klunk, Julie Price, Chet Mathis, Eric Reiman, and Clifford Jack on 27 April 2005.

Bill Klunk
Maybe we can have Cliff give us a short introduction to the Alzheimer Disease Neuroimaging Initiative (ADNI) (see ARF related news story on ADNI).

Clifford Jack
I am on an ADNI phone conference at the same time, so it is hard for me to type anything long.

Bill Klunk
While Cliff is busily typing away, we could take other questions or suggestions.

Chet Mathis
Hank, where does SPECT amyloid imaging in humans stand?

Hank F. Kung
We are doing I-123 IMPY now (IMPY, or 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2-a]pyridine, is a thioflavin derivative that has binding affinity for Aβ in solution and in postmortem AD samples). (See Kung et al., 2002.) The data look good but we are not ready to publish yet. Bill, what's the status of your Pittsburgh compound B (PIB) study in AD patients? (See ARF related news story on PIB imaging).

Bill Klunk
Dick, only PET has imaged amyloid in humans, but Cliff Jack has shown some promising results [for MRI] in mice, which could be applied in human studies once the technology catches up. Is this a fair statement, Cliff?

Mikolaj Pawlak
How about PET-PIB imaging for mild cognitive impairment/amnestic mild cognitive impairment (MCI)? Are there any differences between those two groups?

Bill Klunk
Disease-stage studies are just beginning, but we know if there's a lot already there by the MCI stage. We haven't done enough MCI versus MCI amnestic to know if there is a difference, at least in Pittsburgh.

Mikolaj Pawlak
Thanks, Bill.

Eric Reiman
Bill, the pattern of PIB deposition nicely mirrors the pattern of hypometabolism and hypoperfusion (e.g., precuneus>parietal>frontal). Any chance the PIB measurements are influenced by blood flow (radiotracer delivery)?

M. Koller
Bill, do you have any longitudinal data to assess potential change over time?

Bill Klunk
We will perform our first longitudinal studies in the coming weeks; the subjects just reconsented.

James Ottinger
Bill, how long will you follow those subjects?

Bill Klunk
James, we'll follow at least five years and will keep going as long as there's a good reason to, and the subjects are agreeable.

M. Koller
Bill, in the longitudinal study, what is the time interval between scans you are planning to assess change over time?

Bill Klunk
Marty, the first patients will have an interval of about two years. After that, the interval will be 1 year.

Keith Johnson
Bill/Chet/Julie, we have now done 13 subjects at Massachusetts General Hospital (MGH); are you using 15 mCi and imaging for 45 minutes, or do you think it can be fewer Curies and shorter exposure?

Betty Tuller
Bill and Chet, what is the maximum time between synthesizing the tracer and injection to ensure a decent PET image?

Chet Mathis
Betty, the stability of the tracer is good for 60 min and as long as there is 10-15 mCi for injection and a minimum specific activity of 300 Ci/mmol (at Pittsburgh), it should be fine.

Julie Price
Keith, are you scanning 45 to 90 or 0 to 45 minutes?

Keith Johnson
Do you routinely acquire from 0 to 90, or do you start at 40 minutes? We are doing 0 to 90.

Julie Price
Yes, 0 to 90 for sure.

June Kinoshita
Addendum to Mikolaj's question: What about functional imaging correlated with PIB?

Mikolaj Pawlak
How about correlation between magnetic resonance spectroscopy (MRS) of the medial temporal lobe (MTL) and PIB concentration?

Bill Klunk
Mikolaj, we haven't looked at MRS versus PIB at this point.

Mikolaj Pawlak
I see.

Bill Klunk
We're waiting for Keith and Reisa to do that!

Reisa Sperling
We are working on it!

June Kinoshita
Great!

Mikolaj Pawlak
Okay, to keep this topic up, how about PIB and MTL atrophy dynamics over time?

Bill Klunk
Mikolaj, we are currently gathering MR structural data on all PIB subjects and will eventually start the atrophy-amyloid correlation analyses.

Mikolaj Pawlak
I see; thanks, Bill.

June Kinoshita
There's a great deal of emphasis on the MTL, but at the Bar Harbor workshop last summer, Bill, you mentioned some posterior cortical and retrosplenial regions may be affected early. Can you discuss that further?

Bill Klunk
June, the precuniform cortex seems to be one of the earliest affected regions, not only for PIB imaging, but also fluorodeoxyglucose (FDG) imaging and cortical atrophy. It plays a major role in processing limbic information.

Clifford Jack
Same with MRS, that is, the posterior cingulate-precuniform is affected early.

Nick Fox
Our serial MRI studies also support early involvement of posterior cingulate and precuneus, including in familial AD.

June Kinoshita
How do the changes in posterior cingulate and precuneus compare with MTL changes? Any sense of which is earlier, which is more sensitive or specific?

Bill Klunk
The MTL amyloid studies postmortem show this to be an area with about one-fifth the amyloid load of cortex. PIB shows a consistently higher MTL retention in AD; the amplitude is much lower. We can't yet really say what comes first until we follow amyloid deposition longitudinally.

Eric Reiman
June, we appear to see the posterior cingulate (PC) and precuneus (PCu) change very early, for example, in young adult ApoE4 heterozygotes, who may be at risk for AD dementia 40 to 50 years later. Generally, hippocampal atrophy is seen later, may parallel the earliest cognitive changes, and may herald the subsequent onset of dementia. As baboon and lesion studies have shown, the FDG PET changes could reflect the density/activity of neuronal terminals projecting from the MTL.

June Kinoshita
Thanks Eric. Are the changes seen in PC and PCu in both the functional and structural realm?

Tom Fagan
Bill, naive question, but what's the status on getting PIB-PET or any other imaging approved for diagnostic purposes?

Bill Klunk
Tom, we need more extensive studies to justify this to the FDA. We just submitted our Investigational New Drug (IND) application this week.

Eric Reiman
In response to the diagnosis question: In September, the Centers for Medicare and Medicaid Services (CMS) approved FDG PET for limited use in the differential diagnosis of dementia. According to the CMS, patients should have dementia and cognitive decline for at least 6 months; clinicians should have completed a comprehensive medical evaluation; and there should be remaining uncertainty about the differential diagnosis between AD and frontotemporal dementia (FTD).

Bill Klunk
Thanks, Eric.

Tom Fagan
Bill, do you have any sense for what is the smallest change in amyloid load you can measure with PIB, percentagewise?

Julie Price
Tom, the intrasubject variability is 5 to 6 percent, and we have detected significant group differences of about 15 percent.

Kathryn Convers
I'm just a student, so this may be a silly question, but I was reading an article the other day that mentioned "living slice autoradiography." Can someone please explain to me what this is and how it works?

Betty Tuller
This is a general question for anyone who can answer. If you are performing an AD study, would you expect to see amyloid degradation within 3 or 6 months? Or is it only logical to assess degradation over year time courses?

Bill Klunk
Betty, I assume you mean with antiamyloid therapies. No one knows; it depends on the type of therapy, I would guess.

Clifford Jack
Bill and Chet, have you done any therapeutic studies in mice with PIB using Brad Hyman's cortical window approach?

Bill Klunk
They showed using the amyloid imaging fluorophore, methoxy-X04, that when plaques dissolve, dystrophic neurites seem to repair themselves.

Clifford Jack
Bill and Chet, maybe you guys have published this, but can you comment on test-retest stability of PIB on short-term serial studies?

Julie Price
The test-retest variability is about 5 to 6 percent; the paper is in press in J. Cerebral Blood Flow Metab. The average test-retest was 10 percent in areas dominated by nonspecific binding, 5 to 6 percent in high-binding areas.

Clifford Jack
Five percent is very good. Bill, is the PIB MTL finding a manifestation of spatial resolution of PET, that is, the same thing that is seen in FDG?

Chet Mathis
Cliff, the low PIB in MTL is consistent with postmortem studies. Our PET studies are atrophy corrected by MR. Spatial resolution/partial volume does not account for the very low concentration of PIB in MTL.

Bill Klunk
Yes, in relation to the cortex. We are also further exploring the types of amyloid deposits (e.g., fibrillar vs. amorphous) that are best detected by PIB.

June Kinoshita
I'd also like to toss out a question about a study from Nick Fox's group, just published in Neurology (and previously reported at Philadelphia and Sorrento) about the cortical shrinkage that correlates with response to AN1792 (the Elan vaccine). What ideas do you all have to explain this counterintuitive observation? What imaging resources could be used to shed light on what's going on?

Eric Reiman
June, as Nick noted earlier, he's finding increased atrophy rates in this location relatively early in AD. In cross-sectional, voxel-based morphometry (VBM) comparisons, we also see decreased gray matter density in some of the same regions in which we see hypometabolism, though the PET changes are not solely attributable to atrophy and partial-volume averaging. As Mony de Leon has been showing, these VBM procedures may not be as good at looking at hippocampal gray matter atrophy, because of some spatial standardization challenges.

Tom Fagan
Nick is here, so he might offer some thoughts.

June Kinoshita
On both questions…take it away, Nick!

Nick Fox
As far as the AN1792 study is concerned, I still feel that the simplest explanation is that the volume change represents amyloid loss; of course, there may be multiple mechanisms at play.

Bill Klunk
Nick, I assume you mean amyloid plus surrounding water and tissue reaction, because there's not enough mass of amyloid to explain this by itself.

Clifford Jack
Another possibility is that those who mounted an antibody response also had encephalitis. Patients with florid encephalitis (and who would be expected to do worse clinically?) were excluded. Patients with a low level of encephalitis who later improved clinically due to amyloid reduction had shrinkage of the brain due to encephalitis.

Nick Fox
I think there are a number of experiments that can be done to help separate out some of the alternatives. We are in the midst of measuring cerebellar and pontine changes to check for a simple hydration change, which I don't believe.

June Kinoshita
I believe the responders had decreased CSF tau (phospho-tau?). Was there a similar correlation with CSF Aβ 40/42 ratios?

Hank F. Kung
Is there any postmortem data to support the reduction of Aβ?

Bill Klunk
Hank, four studies have been reported; three show focal amyloid reduction. The fourth, done very early in the treatment course, shows microglia filled with amyloid.

Nick Fox
Bill, the question of the volume (as opposed to mass) is interesting! The autopsy studies using stereology suggest that amyloid accounts for up to 10 percent of some cortical regions. There is a relative paucity of data on the volume occupied by amyloid; one has to remember that plaques contain things other than pure amyloid.

Bill Klunk
Very true, Nick.

Eric Reiman
I'm betting it's the removal of water along with amyloid loss rather than encephalitis that accounts for the reduction in brain volume.

Clifford Jack
Eric, you could be right, but I doubt that the encephalitis was an all-or-nothing phenomenon. I am sure there were varying grades of severity in the study population.

Nick Fox
Eric, I agree it is very difficult to exclude that possibility, but I don't see how encephalitis would explain the dissociation between volume loss and lack of cognitive deterioration. Also, I don't think that subclinical encephalitis can account for the changes. For a start, the baseline scans were done before dosing.

Clifford Jack
Nick, I am not a strong advocate, but threw out encephalitis as a possible idea. The idea is that some level of encephalitis is a requirement in order to see any amyloid reduction. The cognitive deterioration due to encephalitis in those with a large amyloid reduction effect would be overcome by the benefits to cognition of amyloid load reduction—it's an idea.

Nick Fox
Cliff, I think that mixture of effects is plausible.

Reisa Sperling
Nick, you also found reduction in hippocampal volumes (albeit less than global) which is not loaded with amyloid per PIB (and some postmortem studies). What do you think regarding MTL changes?

Nick Fox
What we really needed was a number of scans (as was planned), rather than just two, in order to assess the time course.

June Kinoshita
Could there be indirect effects that AN1792 has on microglial responses?

Nick Fox
June, yes, I think a contribution of reduced microglia is another possibility.

June Kinoshita
There is a new method for imaging microglial activation. I'm waiting for Brad Hyman's group to apply that to their in vivo imaging system! (See ARF related news story.)

Jessica Andrews
Eric, what do you make of all the other metabolic reductions in young ApoE4 heterozygotes you and colleagues reported in your recent paper, for example, lateral parietal/frontal splotches? (See Caselli et al., 2004.)

Eric Reiman
Jessica, this pattern of reductions has been reproduced following MTL lesions in baboons, raising the possibility that it reflects projections from that area. Still, these changes occur very early—before the development of plaque and all by an isolated tangle, raising the question about what underlying brain changes might participate in the subsequent development of AD histopathology.

Jessica Andrews
Eric, thanks. And apparently atrophy is present early on in these non-MTL areas, so it raises the question that MTL, parietal projections might not account for all of the metabolic reductions.

Clifford Jack
Jessica, if you do VBM maps, you see the same reduction in brain volume with MRI that Eric first described in the posterior cingulate.

Nick Fox
Eric, could the ApoE4 related differences reflect a phenotypic difference—from a very early age?

Eric Reiman
Nick, our young adult findings raise more questions than answers. But, it is indeed possible that they develop earlier than young adulthood and are even congenital. What's interesting is that these reductions predict the locations of progressive cerebral glucose metabolism (CMRgl) decline and amyloid accumulation a few decades later.

June Kinoshita
I also want to ask you all to suggest a wish list or priority list for new studies using existing imaging technologies, and also for novel imaging targets that the field needs to elucidate early molecular mechanisms, etc.

Bill Klunk
I'd wish for a tangle-specific tracer!

June Kinoshita
Any progress there?

Bill Klunk
No, not in Pittsburgh. We haven't tried anything along those lines.

June Kinoshita
I've wondered how readily one can get a tracer into neurons to label intraneuronal tau aggregates. Is that one of the challenges?

Bill Klunk
June, not really; once you cross the blood-brain barrier (BBB), the rest should be downhill.

Nick Fox
I'd wish for us to be able to image synapses, as well, but failing that, I'd settle for studies in which we combine amyloid and tangle tracers with structural brain changes. I'd also love to be able to visualize amyloid using structural MRI.

June Kinoshita
Nick, is functional imaging a reasonable surrogate for synaptic changes, or are there more specific molecular targets that you fantasize about?

Mikolaj Pawlak
Has there been any progress in imaging amyloid using MRI?

Clifford Jack
The paper by Saido et al. used a fluorine MRI tracer—it was hard for all of us to understand—but it is definitely interesting.

Nick Fox
June, since we were asked for a wish list, I would still include markers of synaptic integrity in addition to the valuable information from functional imaging.

June Kinoshita
Nick, what would be your top candidates for markers of synaptic integrity?

Eric Reiman
June, whereas FDG PET provides some information about synaptic density, those measurements can be confounded by synaptic activity, glial density, and metabolism, and so on. Something like a synaptophysin marker (or some other synapse-specific receptor) would be great.

June Kinoshita
I agree. Who's working on that?

Nick Fox
June, I agree with Eric, but it is a wish list, so a lot of latitude is allowed. Isn't it?

June Kinoshita
Yes, a lot of latitude!

Bill Klunk
Good-bye from Pittsburgh; we have to run to another meeting.

Eric Reiman
Before I sign off, my thanks to Bill, Nico, and Tom for organizing the chat!

Mikolaj Pawlak
Thanks to everybody.

June Kinoshita
Thanks to the Pittsburgh group and everyone! See you at our next live chat.

Background

Background Text
By Bill Klunk

Imaging is currently the most promising tool for the early diagnosis and monitoring of Alzheimer disease (AD). PET (positron emission tomography) can build high-resolution maps of brain activity and amyloidbeta plaques, while magnetic resonance imaging (MRI) can be used to detect subtle changes in tissue composition. Four relatively recent developments have focused much attention on the capabilities and roles of neuroimaging in AD research.

The Centers for Medicare and Medicaid Services (CMS) has just given limited approval for the reimbursement of FDG-PET in the diagnosis and treatment of mild cognitive impairment (MCI) and early dementia in elderly patients for whom the differential diagnosis includes neurodegenerative diseases.

The launch of the "Alzheimer's Disease Neuroimaging Initiative" (ADNI), a $60 million multi-center effort jointly funded by NIH and the pharmaceutical industry. Details of this large initiative can be found on the ADNI website. See ARF related news story.

Reports from research groups at University of California, Los Angeles (See ARF related news); University of Pittsburgh, Pennsylvania and Uppsala University (See ARF related news); and the University of Toronto and University of Pennsylvania (Verhoeff et al. 2004) demonstrating that PET radiotracers are capable of imaging amyloid pathology (and possibly neurofibrillary tangle pathology) in living subjects.

What do these developments mean for the clinician, the basic researcher, the patient? This discussion will focus on these latest developments and the current state of affairs of AD imaging. For example, which imaging protocol is best suited to AD? Should we be focusing on PET imaging of Aβ, or is MRI likely to be more informative? What questions will ADNI be able to answer? Will it deliver an imaging standard that will be widely accepted? Are there new potential biomarkers out there or new Aβ ligands that can be imaged? And how do we go about finding them?